Many pharmaceutical delivery systems are known in the art which are designed to either delay the release of the drug until the system reaches a particular region of the digestive tract or they are designed to gradually release the drug immediately after oral administration. Enteric formulations are designed to prevent any release of the drug for bioavailability until the delivery system reaches the intestine. These are generally designed for those pharmaceuticals that cause stomach irritation or distress.
Normally, pharmaceuticals that are highly soluble irrespective of the pH of the surrounding environment can be formulated into sustained release delivery systems relatively easily. The delayed release properties can be attained by several methods. On the one hand, the drug can be embedded into a matrix of other excipients which are relatively water insoluble and hence, dissolve slowly so as to release the drug to the digestive system slowly. Another method is to shape the drug and excipients into granules or pellets as an active core which are then coated with a substance that dissolves slowly. Usually, these methods produce a delivery system that dissolves either entirely in the stomach or intestine but not both.
The other drawback with many of these sustained release delivery systems known in the art is the fact that not all of the drug becomes bioavailable during its passage through the digestive tract and it eventually becomes lost and expelled through the feces. Attempts have been made to get around these problems by mixing the drug with an excipient and then either forming a core material comprised of the drug excipient mixture or by coating an inert core such as a non-pareil seed with the drug/excipient mixture followed by a coating of the entire pellet with a thin polymer film.
A major problem in the coating of the core granules by the methods of the prior art is the need to dissolve the coating materials in organic solvents prior to their application. These solvents are not only expensive but dangerous in that they are highly explosive. They also pose health and environmental problems in that most are highly toxic.
U.S. Pat. No. 4,138,475 to McAinish et al discloses a sustained release formulation for propranolol or pharmaceutically acceptable salts thereof whereby the drug is mixed with non-water swellable microcystalline cellulose and formed into spheroids. These are then coated with a heavy film of hydroxypropyl methyl cellulose (HPMC) and or a plasticizer which prevents any release of the drug in the stomach. Needless to say, not all of the drug becomes bioavailable in the small intestine either.
U.S. Pat. No. 4,837,030 to Valorose et al discloses a sustained release delivery system for tetracycline compounds designed to release a minor amount of the drug slowly in the human stomach and then rapidly release the remainder in the small intestine. This is accomplished by mixing the drug with one or more of a number of excipients such as microcrystalline cellulose, polyvinylpyrrolidone (PVP), carboxymethyl cellulose, etc., and a binder such as gelatin which is then either extruded into a spherical pellet or coated about a non-pareil seed. The pharmaceutical core pellet may then be coated with a thin polymer or left bare; in either case it is only 60-90% released in the course of its passage after ninety (90) minutes.
U.S. Pat. No. 4,832,958 to Baudier et al reveals a galenic form of prolonged release verapamil and its salts by mixing the drug with a wetting agent such as fatty acid esters, lecithin, sucrose, mannitol or sorbitol and then spheronizing or granulating the mixture into micro-granules. These are then coated with a microporous membrane comprised of a polymer such as Eudragit.RTM. E30D, (Rohm Pharma GmbH, Weiterstadt, West Germany), HPMC phthalate and other wetting agents, plasticizers and the like. The formulations are designed to withstand adverse environmental conditions during storage such as high temperatures. The formulation is enteric by nature and the drug does not become bioavailable until the system reaches the small intestine.
U.S. Pat. Nos. 4,795,644 and 4,418,183 to Zentner disclose delivery systems for the controlled release of drugs that is not pH-dependent through the modulation of the release of a core drug through a microporous wall coating using charged, insoluble resins that bear an electrostatic charge that is identical to that of the drug. The charged resin is water insoluble and non-diffusible through the microporous wall while the active drug is diffusible and water soluble. The charged resins may be either anionic or cationic in nature, and include polystyrene, epoxy-amine phenolic or methacrylic backbones and release the drug through the microporous wall according to the osmotic pressure, not the pH of the external environment. This allegedly allows for the tailoring of a whole range of release rates according to the type of drug used.
U.S. Pat. No. 4,438,091 to Gruber et al discloses a composition for the delayed release of bromhexine comprised of a mixture of the bronchodialator with an acid such as fumaric or tartaric acid which is compressed into a spherical tablet and coated with lacquers that are insoluble in gastric juices and soluble in intestinal juices. These comprise copolymers of acrylic acid and methacylic acid esters. Whereas the drug is generally insoluble at the higher pH values of the intestine and would be absorbed too quickly at the lower acidic pH conditions of the stomach, the acidic matrix prevents quick dissolution early and yet promotes the drugs bioavailability further downstream in the digestive tract.
European Patent Appln. No. 0,035,780 to Sekigawa et al discloses a process for the preparation of enterosoluble drugs by coating a solid dosage form of the drug with hydroxypropyl methylcellulose phthalate or acidic succinyl and acetyl esters of HPMC. Triethylcitrate is added as a plasticizer which aids in the binding of the coating material to the core pellet. The coating then resists dissolution in the stomach but completely dissolves in the small intestine.
European Patent Appln. No 0,273,005 to Ventouras discloses a water dispersible tablet comprised of an active pharmaceutical core material, a pH dependent disintegrant such as crospovidone (N-vinyl-2-pyrrolidone) or croscarmellose and a water-swellable agent such as guar gum, alginates, dextran and the like. Once contacted by moisture in the human oral cavity, the swellable material absorbs water and becomes gel-like, aiding passage through the oral cavity and throat. Once the delivery system reaches the acidic pH of the stomach, the disintegrant breaks apart immediately, releasing the drug for complete bioavailability.
None of the aforementioned formulations however, are truly semi-enteric formulations whereby the active pharmaceutical is dispersed slowly and continually from the early stages of the digestive tract throughout its passage in the stomach and small intestine so as to become 100% bioavailable. Moreover, none of the prior art references and formulations provide for the gradual and controlled release of an active pharmaceutical whose bioavailability is evenly distributed over time.
It is an object of the present invention to provide a controlled, semi-enteric formulation of an active pharmaceutical that is slowly and continually dissolved and absorbed throughout its passage through both the gastric and intestinal portions of the digestive system. More specifically it is an object of the present invention to provide an antibiotic formulation that is quasi-enteric in nature, i.e., that is partially bioavailable in both the stomach and the small intestine so as to insure 100% bioavailability in both. In particular, it is an object of the present invention to provide a semi-enteric formulation for an antibiotic which becomes bioavailable throughout its passage in the digestive tract.